Process for the production of thiophane derivatives

ABSTRACT

is produced by the reduction of the compound of the general formula   with hydrogen, in the presence of a sulfur resistant nickel catalyst and one or more of auxiliary catalysts selected from the group consisting of aliphatic, aromatic and aralkyl carboxylic acid, esters of said carboxylic acids, Lewis acid, inorganic acid and solid acid catalyst, in an organic solvent. A thiophane derivative of the general formula

United States Patent 11 1 Enoki et al.

[ PROCESS FOR THE PRODUCTION OF THIOPHANE DERIVATIVES [75] Inventors: Kichiji Enoki; Toshio Yao; Keiichi Ishimitsu, all of Takaoka; Keiichi Tsukashima, Tonami; Eiiehi Ikari, Takaoka, all of Japan [73] Assignee: Nippon Soda Company, Limited.

Tokyo, Japan [22] Filed: Jan. 2, I974 [21] Appl. No: 429,916

[30] Foreign Application Priority Data Dec. 25, I972 Japan... 48-2525 Jan. I). I973 Japan 48-7863 Feb. I), I973 Japan 48 l92l4 Mar. 17. 1973 Japan v. 48-3l 184 July 19. 1973 Japan 48-80478 [52] U.S. Cl 260/309.7; 260/3097 X (Sl Int. Cl. C071) 49/34 [58I Field of Search 260/3097 [56] References Cited UNITED STATES PATENTS 1489236 I l/l949 Goldberg et al. 260/3097 X 2.571.238 lO/l95l Harris et a]. 2579.682 12/1951 Surmiltis 260/3097 FOREIGN PATENTS OR APPLICATIONS 968.724 l2/l950 France loll/309,7

Primary E.\'amincrEthel G. Love Attorney, Agem. 0r Firm-George B. Oujevolk 1 Sept. 16, 1975 (57] ABSTRACT A thiophane derivative of the general formula is produced by the reduction of the compound of the general formula with hydrogen. in the presence of a sulfur resistant nickel catalyst and one or more of auxiliary catalysts selected from the group consisting of aliphatic. aromatic and aralkyl carhoxylie acid. esters of said carhoxylic acids. Lewis acid. inorganic acid and solid acid catalyst. in an organic solvent.

ll) Claims, No Drawings PROCESS FOR THE PRODUCTION OF THIOPHANE DERIVATIVES 4 BACKGROUND OF THE INVENTION The present invention relates to a process for the production of a compound (I) of the general formula (CH. oR,

by the reduction of a compound of the general formula wherein R is aralkyl. and R is hydrogen. alkyl. aryl or aralkyl. and n is an integer of l to 6.

The compound (I) wherein n is 3 or 4 is very useful as an intermediate for the synthesis of biotin (vitamin H).

Hitherto. the compound (I) has not been produced from the compound (II) directly, and was produced by the reduction of a compound (III) of the general formula SUMMARY AND DETAlLS OF THE INVENTION The inventors investigated an industrially advantageous synthesis of a compound (l). namely direct production of a compound (l) from a compound (ll).

Oll

As a result. the inventors found that a compound (I) can be produced directly in a high yield by the reduc tion of a compound (ll) when reducing a compound (ll) with hydrogen in an organic solvent in the present of a sulfur resistant nickel catalyst and one or more of auxiliary catalysts selected from the group consisting of aliphatic. aromatic and aralkyl carboxylic acids, esters of said carboxylic acids. Lewis acid. inorganic acid and solid acid catalyst. Then the inventors came to accomplish the present invention.

The present invention isextremely advantageous as an industrial process. because the compound (I) is directly produced from the compound (I) in a high yield and the sulfur resistant nickel catalyst employed for the present invention is inexpensive and easily obtained.

Many kinds of carboxylic acids. esters thereof. Lewis acids. inorganic acids and solid. acid catalysts may be used as an auxiliary catalyst in the present invention. The preferable auxiliary catalyst is mentioned below.

An aliphatic carho'xylic acid contains 1 to 10 of carbon atom, and the ester of an aliphatic carhoxylic acid is a lower alkyl. phenyl or benzyl ester of said aliphatic carboxylic acid. and an aromatic carboxylic acid is bcn zoic acid or benzoic acid having one or more substituents of lower alkyl. hydroxy. lower alkoxy. amine or carboxy. and aralkyl carhoxylic acid is phenyl acetic acid. phenyl propionic acid and said aralkylcarboxylic acids having one or more substituentsof lower alkyl. hydroxy. lower alkoxy. amine or carhoxy. and esters of said aromatic and aralkyl carboxylic acid are lower alkyl esters thereof. for example. formic acid. acetic acid, propionic acid. caproic acid. caprylic acid. capric acid. crotonic acid. ethyl formate. bcnzyl formatc. ethyl acetate. amyl acetate. phcnyl acetate. methyl propionate ethyl caproate. bemoic acid. toluic acid. salicylic acid. phenyl acetic acid. phenyl propionic acid. aminohenzoic acid. phthalic acid. isophthalic acid. methyl benzoate. dimethyl phthalate or the like.

Lewis acid is. for example. aluminium chloride. zinc chloride. stannic chloride. ferric chloride. titanium tetrachloride. or the like. lnorganic acid" as used herein means. for example. sulfuric acid. hydrochloric acid. phosphoric acid or the like. A'solid acid catalyst is. for example. silica. almina. silica-almina. silica-magnesia or the like.

A mixture of more than two kinds of the auxiliary catalyst may be also used.

Each auxiliary above-mentioned has its own addition amount. An addition amount of an auxiliary catalyst is generaly at least 0.5 wtf/z. preferably l to ll) wt?! of the amount of'a starting material. Even if an addition amount is less than 0.5 1.7:. the reaction may he carried out but the rate of the reaction is slow.

in general. the addition amount of an auxiliary catalyst is mentioned above. but in case of using an inorganic acid. a smaller amount may serve the purpose. namely. an addition amount of an inorganic acid is preferably 0.5 to l wt.7(. On the contrary an addition amount of a solid acid catalyst is preferably H) to 40 wt.7r.

Special high purity is not required of an auxiliary catalyst employed in the present invention and a product on the market may be usedwithout any treatment.

The sulfur resistant nickel catalyst employ ed for the present invention may be used by itselt as well as in a form where it is supported on a carrier. An addition amount of said nickel catalyst is more than 1 wtfi.

preferably 5 to St) wtfi of an amount of a starting ma' terial. Even if the amount of sulfur resistant nickel catalyst is less than I wt.' the reaction may be carried out but the rate ofthc reaction is so slow that the reaction time becomes long.

An ordinary organic solvent may be used as a solvent of the present invention unless it is inactive for the present reaction and does not act as catalyst poison. For example. aliphatic acid such as acetic acid, propionic acid, caprylic acid or the like, aliphatic alcohol such as methanol, ethanol or the like. ester of aliphatic acid such as ethyl formate. methyl acetate. ethyl acetate. amyl acetate. phenyl acetate, methyl propionate. benzyl form-ate. ethyl caproate or the like, ester of aromatic carboxylic acid such as methyl benzoate or the like, aromatic hydrocarbon such as benzene, toluene. xylene or the like. cyclic compound such as cyclohcro ane, dioxane or the like, and ketonc such as acetone. methyl ethyl ketone or the like may be used as solvent.

An employed amount of solvent is in the range of l to H) times. preferably 3 to 6 times of the starting mate rial by weight. As a matter of course, the solvent may be used in an amount of more than ll) times, but it is industrially undesirable. A mixed solvent may. of course. be used.

When a compound similar to the aforementioned auxiliary catalyst is used as a solvent as a matter of course. it is unnecessary to add further the auxiliary catalyst. because it is considered that the auxiliary catalyst the employment of which has a distinctive character of the present invention. is already added.

The reaction temperature is generally in a range of 00 to 200C. preferably ltltl" to 150C. though it depends upon a kind of a starting material and other reaction conditions.

The reaction time is generally in a range of l to [0 hours and is in a range of 2 to 4 hours under preferable conditions.

The pressure of hydrogen is generally more than kg/cm'-', preferably 40 to Ztlt] kg/em, more preferably RU to I50 kg/cm'-'. though it depends upon a kind of a starting material and other reaction conditions.

When a reaction temperature is lower than b(l(.'. the rate of the reaction is too slow and the yield decrease. When the reaction temperature is higher than ZUH('. the starting material and the product tend to decompose and heating higher than the reaction requires is economically undesirable.

When the pressure of hydrogen is lower than 3H kg/cni the rate of reaction is too slow. Applying a higher pressure than ZUU kg/cm is economically and industrially undesirable. Such a higher pressure is not required for the present invention.

The present invention makes possible the prodttction of a compound (I) directly from a compound (II) in a high yield and it is industrially ad antagcous process. The yield is almost quantitative under desirable conditions.

The following examples are included merely to aid in understanding the invention. and variations may be made by one skilled in the art without departing from the spirit and scope of the invention.

EMBODIMt-QNTS OF THE INVENTION EXAMPLE I A mivture of Ill g. of 3.44l'3'-diben/yl-I'ketoimida/olido )-Z-liy1lro\y-( w-etho\y propy l t-thiophanc.

ml. of acetic acid and 1.5 g of sulfur resistant nickel catalyst was placed in an autoclave made of SUS32, and a hydrogen pressure-of 80 kg/cm applied. The temperature was increased to l4()C and the reaction was carried out during 4 hours. Then the catalyst was removed by filtration and acetic acid was removed by distillation, and 3,4-( l '.3'-dibenzyl 2-ketoimidazolido)-2-(w-ethoxypropyl) -thiophane was obtained. The yield was quantitative.

(Identification of the product) The total amount of the crude product was dissolved in 50 ml. of acetic acid solution containing l87 hydrobromic acid by weight and allowed to react at a temperature of C during 3 hours. Then, it was evaporated to dryness under reduced pressure. The residue was washed twice with benzene and recrystallized from water to yield 8.6 g. of 3,44 l ',3 'dihenzyl-2'-keto-imidazolido l .2- trimethylene-thiophanium bromide. The product was plates melting point of 220 to 222C. The yield was 82.4% to the starting material having hydroxy group.

Therefore, it was identified as 3.4-( l'.3'-dibenzyl-2'- keto-imidazolido )-2-( urethoxypropyl )-thiophane which was one of the objective compounds of the present invention had been produced in a yield of more than 82.4%.

EXAMPLE I A mixture of ll) g. of 3.44 l'.3'-dibenzyl-2'-ketoimidazolido) -2-hydroxy urethoxypropyl l-thiophanc. 40 ml. of toluene. 0.4 g. of acetic acid and 2 g. of sulfur resistant nickel catalyst was allowed to react and treated in the manner described in Example I. Then. 3.44 l',3'-dibenxyl-2'-keto-imidazolido) -Z (w-ctho. ;ypropyl )-thiophane was obtained. The yield was quantitative.

(ldentitication of the product) The reaction for the identification of the product was carried out as in Example l to yield 8.4 g. of 3,44 l'.3'-dibenzyl-2'-ketoimidazolido l .Z-trimethy lene-thiophanium bromide in a yield of 80.5% to the starting material having hydroxy group. lts melting point was 3Zll to 122C.

EXAMPLE 3 A mixture of IS g. of 3.-l-( l'J'-dibenzyl 2'-ketoimidazolidol thiophane, ml. of acetic acid and 3 g. ofsulfur resistant nickel catalyst was placed in a autoclave made of SUSBZ and a hydrogen pressure of kg/cm" applied. The temperature was increased to ISUC and the reaction was carried out during 4 hours. Then after removing the nickel catalyst by filtration and removing solvent by distillation. the residue was recrystallized from a mi ture of ether and petroleum ether to yield l-H g. of 3.44 l'.3'-diben7yl-Z'-keto-iniida7olidol -1-(wbeniylovybutyl)thiophane. The yield was 97.3 The product was colorless scale crystal and had a melting point of 50 to 58C.

EXAMPLE 4 A mivturc of IN g of 3.44 l'.3'-dibenzyl-Z'ketoimida/olido )-Z-hydro\y -t m-phenoyy butyl lthiophane. l g. of formic acid. 4U ml. of \ylenc and l g. of sulfur rcsistant nickel catalyst was allo cd to react as In l:\- ample to yield oily 3.44 l ,3"tlllh ll/\l': l'itflO- iniida/olulo tZ-(w pheno ybutyl l-thiophanc. llic y'ield \\.|s quantitative (Identification of the product) The total amount of the crude product above-mentioned was dissolved in 50 ml. of xylene. After the solution was cooled in a dry ice-methanol bath 60 ml. of liquid ammonia was added to the solution. Then I g. of metallic sodium was added with stirring, and when it was confirmed that blue color did not disappear a small amount of ammonium chloride was added in order to decompose excess metallic sodium. After evaporation of liquid ammonia, 5% aqueous sulfuric acid and other were added to the residue and the product was removed by filtration and washed with water and recrystallized from ethanol to yield 6.5 g. of 3.4-(N-monobcnzyl- 2-keto-imidazolido)-2-( w-phenoxybutyl)-thiophatte in a yield of 82.9% to the starting material having hydroxy group. Its melting point was 185 to 186C.

EXAMPLE 5 A mixture of It) g. of 3.4-(l',3' dibenZyl-2'ketoimidazolido )-2-hydroxy-( m-methoxybutyl l-thiophane. 50 ml. of propionic acid and 2 g. of sulfur resistant nickel catalyst was allowed to react as in Example I. to yield 3,4-( l ,3 -dibenzyl-2'-ketoimidazolido 2-(wmethoxybutyl)-thiophane. The yield was quanti tative.

(Identification of the product) The total amount of the crude product above-mentioned was dissolved in ml of xylene, and 60 ml. of liquid ammonia was added with cooling in a dry ice-methanol bath. Then l.l g. of metallic sodium was added to the solution with stirring. and when it was confirmed that blue color did not disappear, a small amount of ammonium chloride was added in order to decompose excess of metallic sodium. After evaporation of liquid ammonia. ether and 571 aqueous sulfuric acid were added to the residue. and the product was removed by filtration and washed with water and recrystallized from a mixture of acetone and ether to yield 6 g. of 3,4-(N-monobeniyll'-kctoimidazolido)-2(w-methoxybutyl)-thiophane in a yield of 79.7% to the starting material having hydroxy group. The product was needles and had a melting point of 143 to l44C EXAMPLE 6 A mixture of It] g. of 3,44 l '.3'-dibenzyl-2' ketoimidazolido )-2-hydrox y=( w-ethoxypropyl )thiophanc. 50 ml. of ether acetate and 2 g. of sulfur resistant nickel catalyst was placed in a autoclave made ot SUS32 and a hydrogen pressure of 80 kg/cm applied. The mixture was allowed to react at a temperature of I5()C. for 4 hours and then the reaction mixture was treated as in Example I to yield 3.4-( l ',3-dibenzyl-2-kctoimidazolido)-2'(w-ethoxypropyl)-thiophanc. The yield was quantitative.

(Identification of the product) The reaction for the identification of the product was carried out as in Example l to yield 8.5 g. of 3.4-( l',3' diben2yl-2' kctoimidazolido l .2 trimethylene-thiophanium bromide in a yield of H.619 to the starting material having hydroxy group. The product was plates and had a melting point of 220 to 222C.

EXAMPLE 7 A mixture of H] g. of 3,4-(l',3'-dibenzyl-2"ketoimidazolo )-2'hydroxy-( w-cthoxypropyl )-thiophane 50 ml. of phenyl acetate and 2 g. of sulfur resistant nickel catalyst was allowed to react and treated as in Example o to yield 3,4-( l ',3'-dihenzyl- 2 '-keto-imidazolido )2-( w-ethoxypropyl )-thiopanc.

(Identification of the product) The reaction for the identification of the product was carried out as in Example l to yield 3,44 l.3'dibenzyl-2'-kctoimidazolido)-l.2-trimethylenethiophanium bromide in a yield of 83% to the starting material having hydroxy group. lts melting point was 220 to 222C.

EXAMPLE 8 EXAMPLE 9 A mixture. the composition of which was the same as the one used in Example 8 except containing 50 ml. of

bcn'zyl form-ate instead of methyl propioatc. as allowed to react and treated as in Example 8. The desired product 3.4% l'.3'-dihcnzyl- 2'-kcto-imidazolido )-2-( w-benzy loxybutyl |thiophanc (9.2 g.) was obtained in a yield of The product was colorless scale crystals and had a melting point oi- 56 to 58C.

EXAMPII'v l() A mixture of It) g. of 3.44 l'.3'-dibcn2yl2'-kctoimidaiolido )-2-hydro\y-( w-phcnoxybuty l )-thiophane. 50 ml. of ethyl formate and l g. of sulfur resistant nickel catalyst was placed in a autoclave and a hydrogen pressure of 80 kg/cm" applied. The mixture was allowed to react at a temperature of C during 4 hours and then reaction mixture was treated as in Example l to yield oily 3A4 l'.3'-diben7yl-2'-kctt imidazolido )2( urphenoxyhutyl thiophanc.

(Identification of the product) The reaction for the identification of the product was carried out as in [isample 4 to yield 6.4 g. of 3,44N-monohen2yl-2'-kctoimidazolido)-2-(w-phenoxybutyll-thiophanc in a yield of 8 l 5% to the starting material having hydroxy group. Its melting point was to l8hC.

EXAMPLE l l A mixture of l(] g. of 3.44 l',3'-dihenzyl-2'-ketoimidazolido )-2-hydroxy-( w-mcthoxybutyl l-thiophane. 50 ml. ol'amyl acetate and 2 g. of sulfur resistant nickel catalyst was allowed to react and treated as in Example 6 to yield 3.4-(1'.3-dibenzyl-2'-keto-imidazolido)- 2-(m-methoxybutyl)-thiophane.

(Identification of the product) The reaction for the identification of the product was carried out as in Example 4 to yield 6.1 g. of 3.4-(N-monohenzyl-2'-keto' imidazolidolJ-iw-methoxyhutyl)-thiophane in a yield of 81.2% to the starting material having hydroxy group.

The product was needles and had a melting point of l43 to 14C.

EXAMPLE 12 A mixture. the composition of which was the same as the one used in Example 6 except containing 25 ml. of ethyl acetate and 25 ml. of toluene instead ol- 51) ml. of ethyl acetate. was allowed to react and treated as in E ample 6 to yield 3.4-( l '.3 '-dibenzyl-2'-ket0-imidazolidol-l-tw-ethoxypropylHhiophane.

(Identification of the product) The reaction for the identification ol the product was carried out as in Ex ample l to yield 3.4-( l.3'-dihenzyl-2'-ketoimidazolido)- ,2-trimethylene-thiophanium bromide in a yield of 81); to the starting material having hydroxy group. lts melting point was 220 to 222C.

EXAMPLE l 3 A mixture ol H) g. of 3.4-( l,3'-dihenzyl-2-l-:etoimidazolido )-2-hydroxy( wethoxypropyl )ahiophane. 50 ml. ol'caprylic acid and 2 g. of sulfur resistant nickel catalyst was placed in a autoclave and a hydrogen pressure ol- 8U kg/cm applied. The mixture was allowed to react at a temperature of l()(. during 3 hours and then treated as in Example I to yield 3.4-( l'.3'- dihenryl- 2'-keto-imidayolido )'2-( w-ethoxypropyl thiophanc. The yield was quantitative.

(ldentil'ication ol' the product) The reaction for the identification ol' the product was carried out as in Example l to yield 8.7 g. of 3.44 l.3'-dihen/yl 2'-ketoimidavolido l .2-trimethylenethiophanium bromide in a yield of 83.3) to the starting material having hydroxy group. The product was plates melting at 22H to 222C.

EXAMPLE l-l A mixture. the composition of which was the same as the one used in Example l3 except containing ll) ml. ofcaproic acid and 4t) ml. of toluene instead of 50 ml. olcaprylic acid. was allowed to react and treated as in Example 13 to yield 3.4-( l'.3'-dihen/yl-2'keto lfl'lltlilltllltlu )-2*( w-ethoxypropy l )-thiophane.

(Identification of the product) -lhe reaction for the identification ol' the product was carried out as in l".\- ample l to yield 3.-l l'.3'-dihen/yl-2'-kctoimidavolido l .2-trimethylene-thiophanium bromide in a yield ol N; to the starting material liming hydroxy group. lts melting point was 220 to 222C.

EXAMPLE [5 yield a yield of 74.8% to the starting material having hydroxy group. its melting point was 220 to 222C.

EXAMPLE [6 A mixture, the composition of which is the same as the one used in Example 13 except containing l g. of crotonie acid and ml. of toluene instead of 50 ml. of

caprylic acid. was allowed to react and treated as in Example l3 to yield 3.4-( l '.3'-dibenzyl- 2 keto-imidazolido )-2 urethoxypropyl )thiophane.

(Identification of the product) The reaction for the identification of the product was carried out as in Example l to yield 3.4-( l ',3'-dihenzyl-2'-ketoimidazolido)-l .2-trimethylenethiophanium bromide in a yield of 80.871. lts melting point was 220 to 222C.

EXAMPLE 17 EXAMPLE [8 A mixture. the composition of which was the same as the one used in Example 17 except containing 5U ml. olmethyl henzoate. instead of 25 ml. of dimethyl phthalate and 25 ml. of toluene. was allow ed to react and treated Example 3 to yield 3.44 l '3- dihenlyl-2 keto-imidazolido )-2-( w-henly loxyhutyl thiophane. The yield was 94 The product had a melting point of 56 to 58C.

as in EXAMPLE l9 A mixture. the composition of which was the same as the one used in Example 17 except containing 50 ml. ot ethyl caproate. instead of 25 ml. ot'dimethyl phthal ate and 25 ml. of toluene. was allowed to react and treated as in Example 3 to yield 3.4% l ',3'-dihenZyl-2'- keto-imidazolido )2-( urhenzyloxyhutyl )-thiophane. The yield was The product had a melting point 50 to 58C.

EXAMPLE 20 A mixture ol ltl g. of 1-H l'Jalihenzy|2'-ketoimida/olido 2-hydroxy-( w-phenoxy hut l J-thiophanc.

l g. otp-toluic acid. 50 ml. of toluene and 2 g. of sulfur resistant nickel catalyst was allowed to react and treated as in Example l3 to yield oily 3 4-( l'.3'- dihenzy l-2 '-l\'eto-imida/olido )-2-( w-phenoxy hutyl thiophane. The yield was quantitative.

(Identification of the product) The reaction for the identification ol the product was carried out as in Example 4 to yield (m3 g. of 3.44 N'monohenzyli'-keto imida7olido)-2-( urphenoxyhutyl )-thiophane in a yield ol' SW5 1 to the starting material ha\ing h droxy groupv lts melting point was to lls'hf.

LXAMPLI. 2 l

A mixture. the composition ol \\hiclt was the same as the one used in Example except containing 1 g. of B-phenyl propionic acid instead of 1 g. ofp-toluic acid, was allowed to react and treated as in Example 13 to yield 3.4( l '.3'-diben2y1 2 '-keto-imidazolido )-2-( w-phenylhutyl )-thiophane.

(Identification of the product) The reaction for the identification of the product was carried out as in Example 4 to yield 3.4-( N-monobenzyl-Z'-ketoimidazolido)-2-phenoxyhuty1)thiophane in a yield of 79.0% to the starting material having hydroxy group. Its melting point was 185 to 186C.

EXAMPLE 22 A mixture. the composition of which was the same as the one used in Example 20 except containing 1 g. of isophthalic acid instead of 1 g. of p-toluic acid. was allowed to react and treated as in Example 13 to yield 3; 4-( 1,3-dibcnzyl-2'-ketoimidazo1ido)- 2-( w-phenoxybutyl )-thiophane.

(Identification of the product) The reaction for the identification of the product was carried out as in Example 4 to yield 3.4-( N-monobcnzy1-2-ketoimidazolido)-2-(w-phenoxyhutyl)-thiophane in a yield of 81 .571 to the starting material having hydroxy group. Its melting point was 185 to 186C.

EXAMPLE 23 EXAMPLE 24 A mixture. the composition of which was the same as the one used in Example 23 except containing 2 g. of m-amino henzoic acid instead of 1 g. of salicylic acid. was allowed to react and treated as in Example 13 to yield 3.44 1',3'-dibcnzyl-2'-ketoimidazolido 2-( w-methoxyhutyl )-thiophane.

(Identification of the product) The reaction for the identification of the product was carried out as in Example 5 to yield 3.4-(N-monohenzy1-2'-ketoimidazolido)-2-(w-mcthoxybuty1)-thiophane which melted at 143 to 144C. The yield was 79.7% to the starting material having hydroxy group.

EXAMPLE 25 A mixture of l() g. of 3.4-(l.3'dibenzyl-2'-keto imidazolido )-2hydroxy-( w-ethoxypropyl )-thiophane.

2 g. of zinc chloride. 2 g. of sulfur resistant nickel catalyst and 50 m1. of toluene was allowed to react and treated as in Example 13 to yield 3.4( 1'.3'-dibenzyl- 2 keto-imidazolido )-2-( w-ethoxypropyl )-thiophane. The yield was quantitative.

[Identification of the product) The reaction for the identification of the product was carried out as in Ex ample 1 to yield 8.55 g. of 3.4-( l'.3-dihenzy1-2'ketoimidazolido 1 .2-trimethylenc-thiophanium bromide which was plates melting at 220 to 222C. The yield was 81.8% to the starting material having hydroxy group.

EXAMPLE 26 A mixture of 10 g. of 3.4-( 1 ',3'-dihenzyl-2-keto imidazo1ido)- 2-hydroxy-(w-benzyloxyhutyl)-thiophanc. 0.5 g. ofaluminium chloride, 2 g. of sulfur resistant nickel catalyst and ml. of xylene was allowed to react and treated as in Example 8 to yield 9.45 g. of 3.4-( l '.3'-dihenzyl- 2'-keto-imidazolido1-2-(m-henzy1oxyhutyl )-thiophane. The yield was 97.7%. The product was colorless scales melting at 56 to 58C.

EXAMPLE 27 A mixture. the composition of which was the same as the one used in Example 25 except containing 1 g. of titanium tetrachloride instead of 2 g. of zinc chloride. was allowed to react and treated as in Example 13 to yield 3.4-( l ,3 '-dihcnzyl2"keto-imidaxolido 2-( w-ethoxypropyl )-thiophane.

(Identification of the product) The reaction for the identification of the product was carried out as in ample 1 to yield 3.4-( l'.3'-dihen7yl 2'-kctoimidazolido .2-trimethylene-thiophanium bromide which melted at 220 to 222C. The yield was 79.4% to the starting material having hydroxy group.

EXAMPLE 2% A mixture of ll) g. of 3.4-( l',3'-dihcn7yl-2'-kcto imidazolido )-2-h \'droxy-( urphenoxy hutyl l-thiophane. 2 g. ofstannic chloride. 50 ml. ot xylene and 1 g. otsult'ur resistant catalyst was allowed to react and treated as in Example 13 to yield oily 3.4-1 l'.3-dihenzy12'- kCItFImILILIZUIILlU )'2-( m-phenoxyhut l )-thiophanc.

(Identification ol' the product) The reaction for the identification of the product was carried out as in Example 4 to yield (1.3 g. of 3.44N-n'ionohcivyl-l'-kcto imidazo1ido)-2-( w-phenoxyhutyl J-thiophanc which as needles melting at to 186C The yield was N14? to the starting material having hydroxy group.

EXAMPLE 29 A mixture of 10 g. of 3.441.3'-dihcnzy1-2'-ketoimidazolido )-2-hydroxy( w-mcthoxyhuty| )-thiophanc l g. of ferric chloride. 1.5 g. of sulfur resistant nickel catalyst and 50 ml. of xylene was allowed to react and treated as in Example 13 to yield 3.44 1'.3'-dihenzyl- 2'-kcto-imidazolido )-2-( w-mcthoxyhutyl )-thiophane.

(ldentification of the product) The reaction for the identification of the product was carried out as in Example 4 to yield 6.05 g. of 3.44 N-monohenzyLZ'-keto imidazolido 2-( m-methoxyhutyl l-thiophanc which was needles melting at 143 to 144C. The yield was 80. to the starting material having hydroxy group.

EXAMPLE 3() A mixture of 1() g. of 3.4-( 1'.3'-dihenzyl2-kctoimidazolido )-2hydroxy-( wethoxypropyl )-thiophane. 50 m1. of toluene. (1.05 ml. of sulfuric acid and 2 g. of sulfur resistant nickel catalyst was allowed to react and treated as in Example 13 to yield 3.4% 1'.3'-dihen/ yl- 2'-keto-imidazolido )-2-( w-ethoxypropyl )thiophanc. The yield was quantitative.

(Identification) of the product) The reaction for the identification of the product was carried out as in Example l to yield 7.8 g. of 3.4% l '3 dihen/yl-2'-ketoimidazolido l .Z-trimethylcne-thiophanium hromidc which was plates melting at 220 to 222C The yield was 74.8% to the starting material having hydroxy group.

EXAMPLE 3l A mixture of g. of 3.4-(l'.3'dihenzyLT-ketoimidazolido )-2-hydroxy-( wphcnoxyhutyl J-thiophanc. 50 ml. of toluene. 0.05 ml. of phosphoric acid and 3 g. of sulfur resistant nickel catalyst was allowed to react and treated as in Example l3 to yield oily 3.4% 1Z3" dibenZyl-Z'-keto-imidazolido )-Z-( w-phenoxyhutyl thiophane. The yield was quantitative.

(Identification of the product) The reaction for the identification of the product was carried out as in lxample 4 to yield 6.1 g. of 3.4-( N-monohenzyl-Z'- ketoimidazolido )2-( w-phenoxyhutyl i-thiophane which was needles melting at l85 to l86(. The yield was 77.6); to the starting material having hydroxy group.

EXAMPLE 32 A mixture of 10 g. of 3.4% l'.3'dihenzyl-Z'-ketoimidazolido )-Z-hydroxy-( w-methoxyhutyl l-thiophane. 50 ml. of benzene. 0.1 ml. of concentrated hydrochloric acid and 2 g. of sulfur resistant nickel catalyst was allowed to react and treated as in Example l3 to yield 3.4% l .3 '-dihen7.yl-2-kcto-imidazolido Z4w-niethoxyhutyl)thiophanc. The yield was quanti tati e.

(Identification of the product] The reaction for the identification of the product was carried out as in li\- ample 5 to yield 5.8 g. of 3.44N-monohenzyl-Z'-ketoimidazolido )-2-( w-mcthosyhutyl )-thiophane which as needles melting at 143 to l-l-l(. The yield was 77.4") to the starting material having hydroxy group.

liXAMPLli 33 A mixture of l0 g. of 3.44 l'.3"dihenzyl-l'ketoimida/olitlo lhydroxy l w-henly loxyhutyl l-thiophane. 50 henzcne. 4 g. of silica-almina (Trade name Nt'i3l HN. manufactured from Nikki Kagaku (o.) and 2 g. of sul fur resistant nickel catalyst was allowed to react and treated as in lixample 3 etcept that a hydrogen pres sure of I00 kg/cm' was applied.

('olorless scale crystals of 3.-l-( l'.3'-dihcnzyl-Z- ketoiniidawolido l-Z-t m-hcn/yloxyhutyl l-thiophane (811 g.) was obtained in a yield of 889%. Its melting point was 56 to 58C.

What is claimed is:

l. A process for the production of a compound hav ing the general formula wherein R, is hen/y]. and R is selected from the group consisting of alkyl. phenyl and henzyl. and n is an intcger of l to 6. which comprises reducing a starting mate rial selected from the compound having the general formula with hydrogen in the presence of sulfur resistant nickel catalyst and one or more of auxiliary catalysts selected from the group consisting of aliphatic, aromatic and aralkyl carhoxylic acids. esters thereof. Lewis acids, inorganic mineral acids and solid inorganic acid catalysts in an organic solvent or a mixed organic solvent at a temperature of 60 to 200C under a hydrogen pressure of more than 30 kg/cm.

2. A process according to claim 1. wherein the ali phatic carhoxylic acid contains 1 to 10 of carbon atoms. and the ester of the aliphatic carhosylic acid is selected from the group consisting of lower alkyl. phenyl and henzyl ester of said aliphatic earhoxylic acid. and the aromatic carhoxylic acid is selected from the group consisting of benzoic acid and henzoic acid having a suhstituent or suhstitucnts selected from the group consisting of lower alkyl. hydroxy. amine and carhoxy. and the aralkyl carhoxylic acid is selected from the group consisting of phenyl acetic acid. phenyl propionic acid and said aralkyl carhoxylic acids having a suhstituent or suhstituents on the phenyl moiety of said acid selected from the group consisting of lower alkyl. hydroxy. amine and carhoxy. and esters of said aromatic and aralkyl carhoxylic acid are lower alkyl esters thereof. and said Lewis acid is selected from the grotip consisting of aluminium chloride. zinc chloride. stannic chloride. ferric chloride and titanium tetrachloride. and the inorganic acid is selected from the group consisting of sulfuric acid. hydrochloric acid and phospholic acid. and said solid acid catalyst is selected from the group consisting of silica. alumina. silieaalumina and silica-magnesia.

3. A process according to claim 1. wherein R is sclccted from the group consisting of methyl. ethyl. phenyl and hcnyy l.

4. A process according to claim 2. wherein the amount added of the auxiliary catalysts is at least 0.5 wt!) of the amount of the starting material.

5. A process according to claim 4. wherein the ainotlnt added of the auxiliary catalysts is in a range of I to [0 \y'tfi of the amount of the starting material.

6. A process according to claim I. wherein the amount added of sulfur resistant nickel catalyst is more than l will of the amount of the starting material.

7. A process according to claim 6. wherein the amount added of sulfur resistant nickel catalyst is in a range of 5 to 5 wt; of the amount of the starting niaterial.

8. A process according to claim 1. wherein the reaction temperature is in a range of to l50(.

9. A process according to claim I. wherein the pres sure of hydrogen is in a range of 40 to 200 kg/cm "I. A process according to claim 9. wherein the pressure of hydrogen is in a range of X0 to kgi'cm 

1. A PROCESS FOR THE PRODUCTON OF A COMPOUND HAVING THE GENERAL FORMULA
 2. A process according to claim 1, wherein the aliphatic carboxylic acid contains 1 to 10 of carbon atoms, and the ester of the aliphatic carboxylic acid is selected from the group consisting of lower alkyl, phenyl and benzyl ester of said aliphatic carboxylic acid, and the aromatic carboxylic acid is selected from the group consisting of benzoic acid and benzoic acid having a substituent or substituents selected from the group consisting of lower alkyl, hydroxy, amine and carboxy, and the aralkyl carboxylic acid is selected from the group consisting of phenyl acetic acid, phenyl propionic acid and said aralkyl carboxylic acids having a substituent or substituents on the phenyl moiety of said acid selected from the group consisting of lower alkyl, hydroxy, amine and carboxy, and esters of said aromatic and aralkyl carboxylic acid are lower alkyl esters thereof, and said Lewis acid is selected from the group consisting of aluminium chloride, zinc chloride, stannic chloride, ferric chloride and titanium tetrachloride, and the inorganic acid is selected from the group consisting of sulfuric acid, hydrochloric acid and phospholic acid, and said solid acid catalyst is selected from the group consisting of silica, alumina, silicaalumina and silica-magnesia.
 3. A process according to claim 1, wherein R2 is selected from the group consisting of methyl, ethyl, phenyl and benzyl.
 4. A process according to claim 2, wherein the amount added of the auxiliary catalysts is at least 0.5 wt.% of the amount of the starting material.
 5. A process according to claim 4, wherein the amount added of the auxiliary catalysts is in a range of 1 to 10 wt.% of the amount of the starting material.
 6. A process according to claim 1, wherein the amount added of sulfur resistant nickel catalyst is more than 1 wt.% of the amount of the starting material.
 7. A process according to claim 6, wherein the amount added of sulfur resistant nickel catalyst is in a range of 5 to 50 wt.% of the amount of the starting material.
 8. A process according to claim 1, wherein the reaction temperature is in a range of 100* to 150*C.
 9. A process according to claim 1, wherein the pressure of hydrogen is in a range of 40 to 200 kg/cm2.
 10. A process according to claim 9, wherein the pressure of hydrogen is in a range of 80 to 150 kg/cm2. 